Tryptophan, administered to rats, inhibits gluconeogenesis, but increases the activity of hepatic phosphopyruvate carboxylase when assayed in vitro. Quinolinate, a metabolite of tryptophan, inhibits gluconeogenesis in perfused livers, and inhibits phosphopyruvate carboxylase in liver cytosol from tryptophan-treated rats but not from normal rats.Metal The elevated phosphopyruvate carboxylase activity in cytosol of tryptophan-treated rats was lowered in vitro by quinolinate to the same extent as was the activity of the Fe2+-treated enzyme from normal rats. Ferrous iron is proposed as the physiologically important cation and quinolinate the important metabolite responsible for altering the activity of phoshopyruvate carboxylase in vivo following tryptophan administration.Tryptophan administered to rats enhances the activity of several hepatic enzymes that participate in gluconeogenesis. Among these, phosphopyruvate carboxylase responds in an unusual fashion ; the measurable activity is rapidly increased but the reaction catalyzed by this enzyme appears to be blocked in the intact rat 11-31. The observed elevation of P-pyruvate carboxylase activity is the result of two processes, first a rapid activation of existing enzyme and then a slower increase in activity as new enzyme is synthesized [3]. Tryptophan, at levels as high as 1.7 mM, did not affect the enzymic activity in vitro. However, 50 to 100pM MnCl, or FeCl, added to reaction mixtures containing 6 mM MgCI, activated P-pyruvate carboxylase to levels seen with the enzyme from livers of tryptophantreated rats [3]. The P-pyruvate carboxylase from the latter source was not activated by Mn2+ [3].Ray et al. [2] demonstrated that inhibition of gluconeogenesis after tryptophan administration to fasted rats occurred at the P-pyruvate carboxylase step. Metabolite crossover-type plots showed that the concentrations of gluconeogenic intermediates before the P-pyruvate carboxylase step were higher, while metabolites after that step were lower than the Enzyme. Phosphopyruvate carboxylase or GTP : oxaloacetate carboxy-lyase (transphosphorylating) (EC 4.1.1.32).concentrations of corresponding metabolites in livers of control animals. Veneziale et al.[a] perfused isolated livers from fasted rats with various metabolites of tryptophan and found that compounds in the pathway to nicotinic acid ribonucleotide also inhibited glucose production. Quinolinate, the precursor of nicotinic acid ribonucleotide, blocked gluconeogenesis and activated P-pyruvate carboxylase and was suggested to be the agent responsible for the effect of tryptophan.The key role that P-pyruvate carboxylase plays in gluconeogenesis and the need for information on the regulation of this enzyme led to further investigation of the interaction of metal ions and tryptophan metabolites on enzyme activity in vitro. MATERIALS AND METHODSMale albino rats weighing 160 to 200g (Badger Research Corporation, Madison, Wisconsin) were maintained on water and Rockland chow ad libitum. Animals were fasted for 24 h before sacrit...

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